Generic placeholder image

Central Nervous System Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Research Article

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

Author(s): Meena K. Yadav and Laxmi Tripathi *

Volume 19, Issue 1, 2019

Page: [31 - 45] Pages: 15

DOI: 10.2174/1871524919666181122124012

Price: $65

Abstract

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor.

Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1 .

Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

Keywords: Anticonvulsant activity, computational study, neurotoxicity, pharmacokinetic performance, preclinical (in-vivo) studies, quinazolinone derivative.

Graphical Abstract
[1]
Zayed, M.F.; Ahmed, E.A.; Omar, A.M.; Abdelrahim, A.S.; El-Adl, K. Design, synthesis, and biological evaluation studies of novel quinazolinone derivatives as anticonvulsant agents. Med. Chem. Res., 2013, 22, 1529-2050.
[2]
Zayed, M.F.; Hassan, M.H. Design, synthesis and biological evaluation studies of novel quinazoline derivatives as cytotoxic agents. Drug Res., 2013, 63, 210-215.
[3]
Zayed, M.F.; Hassan, M.H. Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents. Saudi Pharm. J., 2014, 22, 157-162.
[4]
Laznicek, M.; Beno, P.; Waisser, K.; Kvetina, J. Quantitative chemical structure-pharmacokinetic data relationships. IV. Relationships between pharmacokinetic data and lipophilicity of iodine-substituted aromatic and aryl aliphatic compounds. Cesko-Sloven Farma, 1985, 34, 353-358.
[5]
Crivori, P.; Cruciani, G.; Carrupt, P.A.; Testa, B. Predicting blood- brain barrier permeation from three-dimensional molecular structure. J. Med. Chem., 2000, 11, 2204-2216.
[6]
Tiwary, B.K.; Pradhan, K.; Nanda, A.K.; Chakraborty, R. Implication of Quinazoline-4(3H)-ones in medicinal chemistry: A brief review. J. Chem. Biol. Ther, 2015, 1, 104.
[7]
Welch, W.M.; Ewing, F.E.; Huang, J.; Menniti, F.S.; Pagnozzi, M.J.; Kelly, K.; Seymour, P.A.; Guanowsky, V.; Guhan, S.; Guinn, M.R.; Critchett, D.; Lazzaro, J.; Ganong, A.H.; DeVries, K.M.; Staigers, T.L.; Chenard, B.L. Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg. Med. Chem. Lett., 2001, 11, 81-177.
[8]
Kumar, P.; Shrivastava, B.K.; Pandeya, S.N.; Stables, J.P. Design, synthesis and potential 6 Hz psychomotor seizure test activity of some novel 2-(substituted)-3-[substituted]aminoquinazolin-4(3H)-one. Eur. J. Med. Chem., 2011, 46, 1006-1018.
[9]
Zayed, M.F. New fluorinated quinazolinone derivatives as anticonvulsant agents. J. Taibah Univ. Med. Sci, 2014, 9, 104-109.
[10]
Noureldin, N.A.; Kothayer, H.; Lashine, E.M.; Baraka, M.M.; El-Eraky, W.; Awdan, S.A. Synthesis, anticonvulsant activity, and SAR study of novel 4-Quinazolinone derivatives. Arch. Pharm. (Weinheim), 2017, 350, 2.
[http://dx.doi.org/10.1002/ardp.201600332]
[11]
Ugale, V.G.; Bari, S.B. Structural exploration of Quinazolin-4(3H)-ones as anticonvulsants: Rational design, synthesis, pharmacological evaluation, and molecular docking studies. Arch. Pharm, 2016, 349, 817-888.
[12]
Porter, R.J.; Kupferberg, H.J. The anticonvulsant screening program of the national institute of neurological disorders and stroke, NIH: History and contributions to clinical care in the twentieth century and beyond. Neurochem. Res., 2017, 42, 1889-1893.
[13]
Jain, D.K.; Singh, A.; Patel, V.K.; Veerasamy, R.; Aggarwal, N.; Rajak, H. Drug design strategies for the discovery of novel anticonvulsants concerned with four site binding pharmacophoric model studies. Cent. Nerv. Syst. Agents Med. Chem., 2017, 17, 30.
[14]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[15]
Wang, Y.; Xiao, J.; Suzek, T.O.; Zhang, J.; Wang, J.; Bryant, S.H. PubChem: A public information system for analyzing bioactivities of small molecules. Nucleic Acids Res., 2009, 37, W623-W633.
[16]
Yap, C.W. PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints. J. Comput. Chem., 2011, i, 1466-1474.
[17]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. AdmetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52, 3099-3105.
[18]
Lipinski, C.A.; Lombardo, L.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46, 3-26.
[19]
Pandeya, S.N.; Yogeeswari, P.; Stables, J.P. Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones. Eur. J. Med. Chem., 2000, 35, 879-886.
[20]
Vogel, H.G. Drug Discovery and evaluation: Pharmacological assay, Berlin; Springer-Verlag: New York, 2002, pp. 696-716.
[21]
Nishi, A.; Liu, F.; Matsuyama, S.; Hamada, M.; Higashi, H.; Nairn, A.C.; Greengard, P. Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. Proc. Natl. Acad. Sci. USA, 2003, 100, 1322-1327.
[22]
McGeer, E.G.; Ikeda, H.; Asakura, T.; Wada, J.A. Lack of abnormality in brain aromatic amines in rats and mice susceptible to audiogenic seizure. J. Neurochem., 1969, 16, 945-950.
[23]
Krall, R.L.; Penry, J.K.; White, B.G.; Kupferberg, H.J.; Swinyard, E.A. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia, 1978, 19, 409-428.
[24]
Swinyard, E.A.; Woodhead, J.H.; White, H.S.; Franklin, M.R. Antiepileptic Drugs; Raven-Press: NewYork, 1989, Vol. III, pp. 989-995.
[25]
Yogeeswari, P.; Sriram, D.; Saraswat, V.; Vaigunda, R.J.; Mohan, K.M.; Murugesan, S.; Thirumurugan, R. Synthesis and anticonvulsant and neurotoxicity evaluation of N4-phthalimido phenyl (thio) semicarbazides. Eur. J. Pharm. Sci., 2003, 20, 341-346.
[26]
Forney, R.B.; Halpien, H.P.; Hughes, F.W. The comparative enhancement of Phenobarbital activity by co-administration of other anticonvulsants. Experientia, 1962, 18, 468.
[27]
Reitman, S.; Frankel, S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol., 1957, 28, 56-63.
[28]
Varley, H. Practical Clinical Biochemistry; CBS Publishers and Distributors: New Delhi, 1988, pp. 236-238.
[29]
Tietz, N. Fundamentals of clinical chemistry,, Saunders Company: USA, 1957, pp. 68-72.
[30]
Toro, G.; Ackermann, P.G. Practical clinical chemistry; st Ed. Little Brown and Company: New York, 1975, pp. 117-125.
[31]
King, E.J.; Armstrong, A.R. A convenient method for determining serum and bile phosphatase activity. Can. Med. Assoc. J., 1934, 31, 376-381.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy